Abstract The goal of this project is to understand how to prevent neurological dysfunction caused by metabolic stress in the brain. Metabolic stress triggered by impaired oxygen delivery is well known to damage the brain in devastating health issues such as stroke, opioid overdose, and traumatic brain injury. The best case scenario after an insult is often permanent disability and, at worst, premature death. When oxygen flow to the brain stops in these conditions, normal neuronal function fails which leads to pathological activity in neural networks. We hypothesize that synergistic improvements in three aspects of neuronal function that cause vulnerability during energetic stress?cellular metabolism, electrical signaling, and ion regulation? will lead to a state of neuroprotection. To test this hypothesis, we use a model circuit with a dramatic ability to shift between states of very low and very high tolerance to energetic stress as a part of adult life, a central pattern generating circuit in the brainstem of frogs. This model is attractive because it allows us to understand how the same group of neurons can modify vulnerable biological processes to transform their function to resist energetic insults that damage the brain in human diseases. We will test our hypothesis with three specific aims: (1) identify metabolic processes that maintain network function during oxygen lack and simulated stroke, (2) determine mechanisms that promote healthy neuronal signaling during energetic stress, and (3) identify changes in ion channels that contribute to ion balance in stress-tolerant neurons. These aims will be carried out with an integrative technical approach that includes high-throughput single-cell molecular biology, patch clamp and circuit-level electrophysiology, and fluorescence imaging microscopy. Thus, the aims of this AREA (R15) proposal will afford diverse training opportunities to undergraduate and graduate students. In sum, as the mechanisms underlying circuit function and metabolism are widely shared across vertebrate animals, we expect our findings to build a framework that informs how to improve neural function during energetic stress in the mammalian brain.